The purpose of this paper is to describe the preparation of hydrocortisone3 (XIV), 11-epi-hydrocortisone (XV), and Reichstein's Substance E diacetate (V) from cortisone4 (VII), or its acetate (111), by an essentially new and facile method which entails the protection of carbonyl groups as ethylene k e t a l~.~ In this connection, Wendler, Huang-Minlon, and Tishler (1) have selectively protected the C-3, and -20 carbonyl groups of cortisone (VII) by semicarbazone formation. Moreover, these investigators demonstrated that cortisone acetate (111) formed only a 3-mono-semicarbazone. This revealed that the C-21 acetate group hindered the condensation reaction a t the neighboring (2-20 position. This steric effect has been noted previously by Mancera (2). Lithium borohydride reduction of cortisone-3,20-di-semicarbazone, followed by acetylation, and hydrolysis of the semicarbazone groupings (exchange reaction with pyruvic acid) afforded hydrocortisone acetate (XVI).Reichstein's Substance S acetate (I) (Flowsheet I) on treatment with excess ethylene glycol (benzene, p-toluenesulfonic acid) afforded a mono-ethylene ketal to which the structure I1 has been assigned. The product exhibited no selective absorption in the ultraviolet region of the spectrum. The coincident rearrangement of the double bond from the C-4 to the -5 position during the formation of ethylene ketals of A4-3-ketosteroids has been discussed previously (3). It is to be noted that here also the C-21 acetate group hindered the condensation of the C-20 carbonyl group with ethylene glycol. Similarly, only a 3-mono-ethylene ketal (IV) was obtained from cortisone acetate (111) (64% yield). However, and Rosenkranz, Pataki, and Djerassi (7b). (This last publication appeared after completion of our work.) 70An lla-hydroxyl group (in contrast to the 118-isomer) is capable of acetylation, as shown by Long and Gallagher, J .
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